Systems and Methods for Delivery of Peritoneal Dialysis (PD) Solutions

ABSTRACT

The invention provides container systems, kits and methods for peritoneal dialysis (PD) solutions. Such a system, for example, includes a first compartment that contains a PD osmotic agent and a second compartment that contains a PD buffer agent. The compartments maintain their respective contents separately from one another for purposes of transport, storage and/or sterilization. However, the compartments are fluidly couplable, so that their respective contents can be combined with one another, e.g., following sterilization of the agents and prior to their introduction into the patient&#39;s abdomen. The invention provides, in other aspects, such systems, kits and methods that provide protective structure which inhibits breaking of a seal prior between the second compartment and an outlet of the system, prior to breaking of a seal between the first and second compartments.

This application is a continuation-in-part of U.S. patent applicationSer. No. 11/829,611, filed Jul. 27, 2007, entitled “Systems and Methodsfor Delivery of Peritoneal Dialysis (PD) Solutions,” which is acontinuation in part of 11/340,403, filed Jan. 26, 2006, entitled“Systems and Methods for Delivery of Peritoneal Dialysis (PD)Solutions,” which is a continuation-in-part of U.S. patent applicationSer. No. 11/046,667, entitled “System and Methods for DextroseContaining Peritoneal Dialysis (PD) Solutions With Neutral PH AndReduced Glucose Degradation Product,” filed Jan. 28, 2005, the teachingsof all of which applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

The invention relates to peritoneal dialysis (PD). In particular, itprovides containers and methods for treating peritoneal dialysissolutions that reduce glucose degradation products (GDPs).

Peritoneal dialysis (PD) is a medical procedure for removing toxins fromthe blood that takes advantage of the semi-permeable membranesurrounding the walls of the abdomen or peritoneal cavity. During a PDprocedure, a solution is introduced into the patient's abdomen, where itremains for up to several hours, removing blood toxins via osmotictransfer through that membrane. At completion of the procedure, thesolution is drained from the body along with the toxins.

An active constituent of the PD solution is an osmotic agent, such asglucose, that creates an osmotic gradient across the peritonealmembrane, allowing exchange of toxins from the blood into the peritonealcavity, as described above. Another constituent is an electrolytecomposition, such as a mixture of sodium, calcium, potassium, chlorine,magnesium, and so forth, which restores and maintains electrolytebalance in the blood. A final typical constituent is a buffering agent,such as lactate and pyruvate, which ensures that the blood pH remains ata physiological norms during the procedure.

A major problem with commercially available PD solutions is the presenceof degradation products. These products, which typically arise duringlong-term storage or sterilization of the solutions, damage theperitoneal wall and can adversely affect proteins elsewhere in thepatient's body.

Attempts to eliminate these degradation products have met some success.An example is the assignee's own U.S. Pat. No. 6,277,815, which utilizesa multi-chamber PVC or polyolefin bag to separate PD constituents duringstorage and sterilization. That notwithstanding, there remains acontinuing need for improved containers and methods for PD solutions toreduce glucose degradation products (GDPs). That is among the objects ofthis invention.

Another object of the invention is to provide such containers andmethods as can be fabricated at low cost.

Still another object of the invention is to provide such containers andmethods as can be fabricated utilizing existing materials andfabrication techniques

Still yet still another object of the invention is to provide suchcontainers and methods as can be provided PD solutions ofphysiologically optimal concentrations and pH levels.

SUMMARY OF THE INVENTION

The foregoing and other objects are attained by the invention whichprovides, in some aspects, a container system for medical solutions suchas peritoneal dialysis (PD) solutions. The invention particularlyfeatures a system which includes a first compartment that contains afirst medical solution, e.g., a PD osmotic agent, and a secondcompartment that contains a second medical solution, e.g., a PD bufferagent. The compartments maintain their respective contents separatelyfrom one another for purposes of transport, storage and/orsterilization. However, the compartments are fluidly couplable, so thattheir respective contents can be combined with one another, e.g.,following sterilization of the agents and prior to their introductioninto the patient's abdomen.

According to some aspects of the invention, the PD buffer agent ishighly concentrated and/or highly alkaline. Thus, the buffer agent canbe about 3-fold higher in concentration than the chemically “Normal”concentration for that agent, preferably 5-fold or higher, morepreferably, 7-fold or higher, more preferably, 10-fold or higher, andstill more preferably, 15-fold or higher. Since conventional,commercially-available PD solution buffer agents are of chemicallyNormal concentrations, the buffer agent according to these aspects ofthe invention can likewise be about 3-fold higher in concentration thanconventional buffer agents, preferably 5-fold or higher, morepreferably, 7-fold or higher, more preferably, 10-fold or higher, andstill more preferably, 15-fold or higher. Examples of suitable PD bufferagents for use in these aspects of the invention include, but are notlimited to, lactate, acetate, and pyruvate. According to related aspectsof the invention, the PD buffer agent has a pH of about 8.0 to about14.0, and, more preferably, a pH of about 9.0 to about 13 and, stillmore preferably, a pH of about 10.0 to about 12.0.

According to related aspects of the invention, the second compartment(in which that PD buffer agent is stored) has a small volumetriccapacity relative to that of the first compartment. Likewise, thevolumetric amount of PD buffer agent is small compared to that of the PDosmotic agent. Thus, for example, where the first compartment is ofstandard clinical use capacity (between 1-5 liters), the secondcompartment is sized between 5 ml-50 ml, and preferably about 7.5-37.5ml.

In still other related aspects of the invention, the ratio of thevolumetric capacity of the first to second compartments is in the rangeof about 20:1 to about 200:1, preferably about 50:1 to about 150:1, andpreferably about 70:1 to about 140:1, preferably about 90:1 to about120:1, and most preferably about 133:1.

According to further aspects of the invention, the PD osmotic agent isat physiological use concentrations, i.e., substantially atconcentrations at which that agent will be introduced into the patient'sabdomen. In related aspects of the invention, those concentrations arebetween 1.5%-4.25% and, more preferably, between 2.0%-4.0% and, stillmore preferably, between 2.0%-3.0%.

The PD osmotic agent, moreover, according to related aspects of theinvention, is at a physiologically low pH, i.e., a pH below that atwhich that agent will be introduced into the patient's abdomen. Inrelated aspects of the invention, those pH levels are between 1.0-6.0and, most preferably, between 1.0-3.0. The PD osmotic agent can be, byway of non-limiting example, a sugar selected from the group consistingof glucose, dextrose, icodextrin, and fructose. In further relatedaspects of the invention, the first compartment can containelectrolytes, in addition to the osmotic agent.

The first and second compartments are, according to one aspect of theinvention, formed in vessels that are fabricated separately from oneanother. Thus, for example, the first compartment can be formed in a 1-5liter glass container (e.g., an infusion bottle) or flexible bag (e.g.,an infusion bag) made, for example, of PVC, polyolefin, polypropylene,or other medical-grade material) of the type typically used to containand/or administer peritoneal dialysis fluids. The second compartment canbe formed in separate container, such as a tube or vial of flexible,moldable or malleable material such as PVC, all by way of non-limitingexample.

In related aspects, the aforementioned vessels adapted so that they canbe directly or indirectly physically coupled to one another to supportfluid transfer between the compartments. Thus, for example, a PVC bag inwhich the first compartment is formed can have a port for receiving, byfusing, bonding, interference-fit, screw-fit, or otherwise, a tube inwhich the first compartment is formed. Alternatively, or in addition,that port can be arranged to receive a needle-like extension, bayonet,or other adapter affixed to such a tube. By way of further example, bothvessels can be adapted to receive opposing ends of a common piece ofmedical-grade tubing.

According to related aspects of the invention, a seal is provided in afluid-transfer path between the first and second compartments to preventcontact between the PD osmotic agent and the PD buffer agent. The sealis temporary and can be broken, e.g., by a patient, health care provideror manufacturer, to permit the agents to mix following theirsterilization and prior to their introduction into the patient'sabdomen. The seal may be formed integrally with either of the vessels,e.g., as in the case of a frangible seal formed in the PDbuffer-containing vial, or otherwise.

Still further aspects of the invention provide a container system for PDsolutions comprising a flexible bag (or glass jar, by way of example)containing a PD osmotic agent and having a standard clinical usecapacity, e.g., in the range of 1-5 liters. The system also has a tubecontaining a PD buffer agent and having a capacity, e.g., in the rangeof 10-15 mls and/or a pH in the range of 10.0-12.0. The bag and tube aredirectly or indirectly coupled via respective ports in each of them. Afrangible member in the tube prevents mixing of the agents until broken,e.g., by a patient, health care provider or manufacturer, followingsterilization of the agents and prior to their introduction into to theabdominal cavity.

Yet still further aspects of the invention provide peritoneal dialysiskits comprising PD osmotic agent-containing and bufferingagent-containing vessels as described above. Such kits can also includetubing and other apparatus for coupling the vessels, as well as forintroducing the PD solution produced thereby to a patient's abdomen.And, those kits can also include apparatus to facilitate sterilizationof the contained osmotic and buffering agents. Moreover, they caninclude apparatus to facilitate breaking of the above-describedfrangible (or other sealing) members, e.g., following sterilization ofthe agents and prior to their introduction into to the abdominal cavity.

Further aspects of the invention provide methods for peritoneal dialysissolutions that contemplate sterilizing a PD osmotic solution containedin a first compartment, sterilizing a PD buffer agent of concentrationand/or pH as described above contained in a second compartment, wherethe first and second compartments are not in fluid communication duringthe sterilization steps. The method further contemplates placing thefirst and second compartments in fluid communication following thesterilization step and mixing their contents with one another, prior tointroducing the mixed contents into a patient's abdomen.

Still further aspects of the invention provide methods as describedabove in which the second compartment (in which that PD buffer agent isstored) has a small volumetric capacity relative to that of the firstcompartment and/or likewise, where the volumetric amount of PD bufferagent is small compared to that of the osmotic agent.

Still further aspects of the invention provide methods as describedabove that include breaking of a seal between the first and secondcompartments and, thereby, allowing their contents to mix following thesterilization stage. This can include, for example, bending and/orsqueezing a semi-rigid tube that contains the buffer agent (and/or thatforms the fluid flow path between the first and second compartments) inorder to break a frangible sealing member that separates that agent fromthe osmotic agent.

Yet still further aspects of the invention provide systems for deliveryof PD solutions as described above adapted to ensure mixing of the firstand second constituents prior to delivery of the resultant PD solutionto the patient. In one such aspect, a system according to the inventioncomprises a first compartment and a second compartment, e.g., for firstand second PD constituents. A first seal prevents fluid transfer betweenthe first compartment and the second compartment, and a second sealprevents fluid transfer between the second compartment and an outletfluid pathway that leads, e.g., to the patient. Protective structure isprovided to deter the patient, his/her health care provider, or others,from breaking the second seal prior to the first seal. This has thebenefit, for example, of ensuring expulsion of at least a portion of aPD agent from the second compartment to the first compartment prior tobreakage of the second seal.

In a related aspect of the invention, that protective structure is acover initially positioned in protective relation to the second sealwhere it inhibits the breaking of that seal. That cover can include aninner passageway and can be slidably disposed to move from the initialposition to a second position, where it does not protect the secondseal. The size and/or shape of the vessel (or portion thereof) thatforms the second compartment restrains such movement—prior to emptyingof the second compartment (at least partially) following breaking of thefirst seal.

In still another aspect of the invention, the second seal is disposedwithin the vessel that forms the second compartment. Fluid or otherpressure from a PD constituent, e.g., a fluid buffer agent, initiallycontained in that vessel inhibits bending, twisting or othermanipulation of it sufficient to break the second seal. Once the firstseal has been broken and the PD constituent has been at least partiallyexpelled to the first compartment (for mixing with the other PDconstituent), the corresponding reduction of fluid or other pressure inthe vessel permits manipulation sufficient to break the second seal.

The first and second compartments, according to other aspects of theinvention, comprise separate chambers of a single vessel, e.g., a“multi-chamber” vessel. Thus, for example, those compartments can formseparate chambers of a bag, tube or other vessel of flexible, moldableor malleable material such as PVC or other medical grade material. Thecompartments can be fluidly coupled by a port (e.g., an aperture, tubingor other fluid transfer path) that is, for example, integral to thevessel, affixed to the vessel or otherwise. As above, a temporary and/orbreakable seal can be provided in that fluid-transfer path to preventcontact between the fluids (e.g., PD osmotic agent and the PD bufferagent) in the respective containers. That seal may be formed integrallywith the pathway, with the vessel or otherwise.

In related aspects, a multi-chambered vessel as described above can beformed to permit at least one of the compartments to be manipulated,e.g., bent, twisted, squeezed and/or folded, at least partiallyindependently of the other. Thus, for example, portions of the vessel inwhich the respective compartments are formed are at least partiallyseparable from one another so that, for example, one portion can befolded and its respective compartment squeezed without substantiallyfolding the other and squeezing its respective compartment—thus, forexample, permitting the user expel liquid from one compartment into theother.

Further related aspects of the invention provide such a multi-chamberedvessel as is formed by stamping, cutting, welding, gluing, or otherwiseprocessing one or more sheets or webs of PVC or other suitable material,e.g., to form a bag-like or other-shaped vessel with the aforesaidcompartments. A vessel so formed can be perforated in one or moreregions between the portions in which the respective compartments areformed. These perforations can be torn by the user to partially separatethose portions from one another and to facilitate independentmanipulation of their respective compartments (as discussed above);before they are broken, the vessel is more easily handled, e.g., forpurposes of manufacture, shipping and handling. In lieu of (or additionto) perforations, the regions can be cut (or otherwise separated) andtacked to the same effect.

Yet still further aspects of the invention provide systems for deliveryof PD solutions as described above that include a diffuser in a fluidpathway between the first and second compartments. Such a diffuser can,for example, facilitate homogeneous mixing of the first and second PDagents, even where they are of different viscosities and/or densities.

Related aspects of the invention provide such systems in which thediffuser facilitates such mixing on expulsion of the PD constituent fromthe second compartment into the first compartment.

Further related aspects of the invention provide such systems in whichthe diffuser comprises multiple apertures disposed within the firstcompartment. Those apertures can have diameters, in one aspect of theinvention, in the range 1.0 mm-1.5 mm. They can, according to stillfurther aspects of the invention, effect angular dispersion of the PDconstituent from the second compartment, upon its expulsion into thefirst compartment.

Still other aspects of the invention provide systems for delivery of PDsolutions as described above in which the vessel (or portion thereof)forming the second compartment folds upon application of force andexpels the PD constituent contained therein in connection therewith. Acover that is provided as the aforementioned protective structurecomprises a slot or other opening that is sized to slide over at least aportion of the second compartment, depending on a quantity of PDconstituent therein.

In related aspects of the invention, the aforementioned slot or otheropening is arranged to slide over at least a portion of the vesselforming the second compartment only if that vessel is at least partiallyfolded, in a manner of butterfly wings.

In related aspects of the invention, the aforementioned slot or otheropening is arranged to slide over at least the portion of the vesselforming the second compartment only after a quantity of the PDconstituent originally contained therein has been expelled therefrom.

In further related aspects of the invention, the slot or other openingis arranged to slide over at least the portion of the vessel forming thesecond compartment only after at least 10%-30% of a quantity of the PDconstituent originally contained in that compartment has been expelledtherefrom.

In further related aspects of the invention, the slot or other openingis arranged to slide over at least the portion of the vessel forming thesecond compartment only after at least 30%-50% of a quantity of the PDconstituent originally contained in that compartment has been expelledtherefrom.

In further related aspects of the invention, the slot or other openingis arranged to slide over at least the portion of the vessel forming thesecond compartment only after at least 75% of a quantity of the PDconstituent originally contained in that compartment has been expelledtherefrom.

Other aspects of the invention provide methods paralleling theoperations described above.

Still other aspects of the invention provides container systems andmethods as described above for other medical and non-medical solutions.

These and other aspects of the invention are evident in the drawings andin the description that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete understanding of the invention may be attained byreference to the drawings, in which:

FIG. 1 depicts a system for containing a peritoneal dialysis solutionaccording to one practice of the invention and includes a break-outportion depicting one of the vessels of that system in greater detail;

FIG. 2 depicts a sequence for sterilizing and administering a peritonealdialysis solution according to the invention;

FIG. 3 depicts a system for containing a peritoneal dialysis solutionaccording to a further practice of the invention and includes abreak-out portion depicting one of the vessels of that system in greaterdetail;

FIGS. 4A-4C depict utilization of the system of FIG. 3 to mix agents ofthe peritoneal dialysis solution (e.g., following sterilization) and totransfer the mixed agents to the patient.

FIG. 5 is a schematic of a frangible seal.

FIG. 6 depicts a system for containing a peritoneal dialysis solutionaccording to one practice of the invention that includes a protectivemember adapted to inhibit breaking of a second seal prior to breaking ofa first seal.

FIGS. 7A-7E illustrate operation of the system of FIG. 6.

FIGS. 8A-8B illustrate an embodiment of the invention incorporating analternate configuration of the second container of FIG. 6.

FIG. 9 illustrates an embodiment of the invention in which thefluid-filled second compartment defines the protective member.

FIGS. 10A-10D illustrate operation of the system of FIG. 9.

FIGS. 11A-11F illustrate configuration and use of the embodiment ofFIGS. 8A-8B.

FIGS. 12A-12E depict use of a container system according to theinvention that includes a diffuser in a fluid pathway between thevessels.

FIGS. 13A-13E depict a procedure for use of the container systemdepicted in FIGS. 12A-12E.

FIGS. 14A-14E are graphs of pH as a function of the outflow volume ofthe catheter of sample systems of the type shown in FIGS. 12A-12E whenused with normally expected operating procedures.

FIG. 15 depicts a multi-chamber vessel for containing a peritonealdialysis solution according to one practice of the invention.

FIGS. 16A-16F depicts a manner of use of the multi-chamber vessel ofFIG. 15.

DETAILED DESCRIPTION

FIG. 1 illustrates a container system for PD solutions according to onepractice of the invention. The container system 10 has a first vessel 12that contains, in compartment 12 a, a PD osmotic agent solution 14. Asecond vessel 20 contains, in compartment 20 a, PD buffer agent solution22. The vessels 12, 20 and, more particularly, the compartments 12 a, 20a are coupled for fluid exchange via port 18 formed in vessel 12, asshown. A temporary seal 24 is provided in the fluid-transfer pathbetween the compartments, also as shown. This prevents contact betweenor mixing of the PD osmotic agent and the PD buffer agent, e.g., untilafter sterilization of the agents. A further temporary seal 26 isprovided in a catheter 28 that leads, e.g., to the patient's peritonealcavity (not shown), and prevents flow of PD solution, e.g., until aftermixing of the sterilized agents.

Illustrated first vessel 12 is a conventional medical-grade PVC hanging“transfusion” bag, as illustrated. In other embodiments it may be ofother configurations and/or comprised of other materials, such as aglass container or other flexible or non-flexible containers (of PVC,polyolefin, polypropylene, or other medical-grade material) of the typetypically used to contain and/or administer peritoneal dialysis agents.The compartment 12 a is formed within the vessel 12 in the conventionalmanner and, in the illustrated embodiment, is of standard clinical usecapacity (e.g., sized between 1-5 liters), though other sizes may beused as well. As indicated above, vessel 12 includes at least one port18 providing a fluid-transfer path to compartment 12 a. This port can beused to transfer agents to and from the vessel 12, e.g., duringmanufacture at the pharmaceutical plant, during mixing of the agents,and/or during administration of the mixed agents to the patient. Otherembodiments may use a greater or fewer number of ports than thoseillustrated and, indeed, may use no ports at all (e.g., where needles orother methods are used to add and remove agents from the compartment 12a).

Illustrated vessel 20 is a tube-like vessel (or miniature bulb or“mini-bulb”) of PVC or other medical grade material suitable forcontaining at least a PD buffer agent. The illustrated vessel issemi-rigid and, therefore, suitable for squeezing or other manipulationby a patient, health care provider or manufacturer, e.g., to facilitatebreaking of the seal 24, extrusion of the PD buffer agent out fromcompartment 20 a and into compartment 12 a, and/or mixing of the PDagents. In other embodiments, the vessel may be of other configurationsand may be fabricated from other materials (e.g., rubber, polyolefin,polypropylene, and/or other medical grade materials). Moreover, thevessel need not be semi-rigid: it may be rigid or flexible, depending onhow the patient, health care provider or manufacturer are expected touse it for purposes of breaking of seal 24, expelling the PD bufferagent and/or mixing of the PD agents Still further, although vessel 20has a tube-like configuration, other embodiments may utilize vessels ofdifferent shapes. Vessel 20 can be formed by a blow molded ordipping-formed bubble in-line with the solution bag outlet. Othermethods for forming the second vessel are possible also, such asformation during the tubing extrusion process (commonly called Bumptubing) or heat forming vessel 20 in pre-extruded tubing.

Illustrated vessel 20 is adapted for direct or indirect coupling withvessel 12 so as to provide a fluid transfer path between compartments 12a, 20 a. To this end, vessel 20 has a proximal end port 25 adapted forfusing, bonding, interference-fit, screw-fit or other coupling withvessel 12, hereby, by way of its port 18, as shown in the drawing. Inother embodiments, fluidic coupling between the compartments 12 a, 20 amay be attained in other ways, e.g., by needle- or bayonet-like adaptersaffixed to either vessel (or its respective port) for receipt by theother vessel.

Vessel 20 is likewise adapted for direct or indirect fluid transfer tothe patient's peritoneal cavity. In the illustrated embodiment, this isby way of a distal port 27 adapted for fusing, bonding,interference-fit, screw-fit or other coupling with catheter 28, asshown. That catheter may lead directly to the peritoneal cavity orindirectly, e.g., by way of filters, heaters and/or other medicalapparatus.

The compartment 20 a of the second vessel 20 has small volumetriccapacity in comparison to that of the first vessel 12. Thus, forexample, where the first compartment 12 a of the illustrated embodimentis of a capacity sized between 1-5 liters, the second compartment 20 ais sized about 5-50 ml, preferably about 7.5-37.5 ml. Thus, it will beappreciated that the ratio of volumetric capacity of the first to secondcompartments is about 20:1 to about 200:1, preferably about 50:1 toabout 150:1, and preferably, about 70:1 to about 140:1, and mostpreferably about 133:1.

Seal 24 is adapted to prevent fluid transfer (or other contact) betweenthe PD agents contained in compartments during manufacture, transport,storage and sterilization of system 10, yet, to permit such fluidtransfer upon breaking of that seal 24 (e.g., by a patient, health careprovider, or manufacturer) for purposes of mixing the agents followingsterilization. In the illustrated embodiment, the patient, health careprovider, or manufacturer need not introduce a foreign object (such as aneedle) to break the seal 24. Rather, this may be accomplished bysqueezing, twisting or other manipulation of vessel 20 and/or port 18.To this end, in the illustrated embodiment, the seal 24 is a frangiblemember disposed between the aforementioned proximal port of the vessel20 and the port 18 and is affixed to (and/or formed integrally with) aninterior fluid-transfer path of one or both of those ports.

Seal 24 can be fabricated from nylon, plastic, or other medical-gradematerial, and can be constructed in the manner of conventional frangibleseals known in the art and commercially available in the marketplace,e.g., from medical supply manufacturers Baxter, Gambro and Qosina. Onepreferred seal 24 is constructed in the manner of the frangible sealcommercially available from Fresenius Medical Care, e.g., as a componentof its Premiere™ Plus Double Bag system. That seal is depicted in FIG.5.

Referring to the drawing, illustrated seal 24 comprises an elongatemember having a head portion 24 a and a tail portion 24 b, as shown. Thelatter comprises a main body 24 c and flanges 24 d which, together,clamp the distal end of port 18 and the proximal end of vessel 20 (asshown), thus, providing physical coupling between the vessels 12 and 20.The tail portion 24 b has a central throughway which permits fluidcoupling between compartments 12 a, 20 a, when frangible bond 24 e isbroken, as discussed below.

The head portion 24 a, shown here of generally mushroom cap shape, iscoupled to tail portion 24 b by frangible bond 24 e. Head portion 24 adoes not include a fluid throughway and, hence, prevents fluid fromflowing between compartments 12 a, 20 a through tail portion 24 b solong as bond 24 e remains intact. That bond 24 e, which may be formed byultrasonic welding, adhesives, interference fit, fusing, integralmolding, or otherwise, breaks upon bending or other manipulation of theseal 24 (e.g., by patient, health care provider, or manufacturer),thereby permitting such flow.

Those skilled in the art will appreciate that FIG. 5 depicts an exampleof a type of seal which can be used in practice of the invention andthat seals of other configurations (frangible or otherwise) whichprevent undesired contact between the PD agents, yet, permit suchcontact to be established by the patient, health care provider, ormanufacturer, may be used instead or in addition.

With reference back to FIG. 1, seal 26 is adapted to prevent fluidtransfer to the patient prior to both sterilization and mixing of the PDagents. As above, the patient, health care provider, or manufacturerdoes not need to introduce a foreign object (such as a needle) to breakseal 26 but, rather, may be accomplish this by squeezing, twisting orother manipulation of vessel 20, the distal port thereof and/or catheter28. To this end, as above, the seal 26 of the illustrated embodiment isa frangible member disposed between the aforementioned distal port ofthe vessel 20 and the catheter and affixed to (and/or formed integrallywith) an interior fluid-transfer path of one or both of those. The seal26, too, can be fabricated from nylon, plastic, or other medical-gradematerial, and it can be formed in the configurations discussed above inconnection with seal 24 (and shown, for example, in FIG. 5).

In the embodiment of FIG. 1, the focus and/or type of manipulationrequired to break seal 26 differs from that required to break seal 24.This prevents both seals 24, 26 from being unintentionally broken at thesame time and, thus, helps insure that the sterilized fluids are mixedprior to their being transferred to the patient. To facilitate this, theseals 24, 26 can be colored differently to alert and remind the user ofthe proper order in which they are to be broken. Those skilled in theart will appreciate, of course, that coloration can be used inconnection with other elements of the system 10, as well.

Referring to FIG. 6, additional structure can be provided to furtherinsure that the seals 24, 26 are broken in the proper order and,therefore, to prevent fluid transfer to the catheter 28 (and anydownstream equipment) prior to sterilization and mixing of the PDagents. That drawing depicts container system 50 of the same generalconfiguration as container system 10 of FIG. 1 (as indicated by likereference numerals), albeit including a protective member in the form ofcover 52 that slides from an initial position, wherein it protects seal26 from manipulation, to a second position, wherein it permits that sealto be broken. FIGS. 6 and 7A-7C show cover 52 in the initial position.FIG. 7D-7E show the cover 52 in the second position.

Referring to FIG. 6, cover 52 is shown in its initial position, disposedin protective relation to seal 26. In this regard, cover 52 is, moreparticularly,

-   (a) disposed in surrounding relation to the distal port of vessel    20, the catheter 28 and/or such other structures of system 50 in    vicinity of seal 26 that (as discussed above) the patient, health    care provider, or other user manipulates in order to break seal 26,    and-   (b) thereby prevents (or otherwise inhibits) breaking of seal 26    prior to breaking of seal 24.

The cover 52, which can comprise nylon, plastic, or other material(medical-grade or otherwise), preferably, in a rigid or semi-rigidformulation, includes an annular or other internal passageway 54 inwhich seal 26, the distal port of vessel 20, and/or proximal portion ofcatheter 28 are initially disposed, as shown in the drawing. Theinternal passageway extends from a distal end 56 to a proximal end 58and, in the illustrated embodiment, has an internal diameter that can,though need not, vary therebetween, e.g., as shown.

An inner diameter of the passageway 54, e.g., at the proximal end 58, issized and shaped to inhibit movement of cover 52 in a distal-to-proximaldirection (e.g., “upward” in the drawing) prior to breaking of seal 24,e.g., when vessel 20 contains its post-manufacture complement of PDbuffer agent solution 22 (and/or other liquids, gasses or solids). Moreparticularly, the inner diameter of that passageway at the proximal end58 is smaller than an outer diameter of vessel 20 prior to breaking ofseal 24 and any of (a) at least some reduction in that outer diameter(via expulsion of a post-manufacture complement of solution 22 and/orother liquids, gasses or solids) from vessel 20—and, preferably, atleast 10%-30% and, still more preferably, at least 30%-50% and, yetstill more preferably, at least 50%—of such reduction, and/or (b) adecrease in resistance to such reduction.

The passageway 54 can have a larger inner diameter at the distal end 56than at the proximal end 58, as shown in the drawing. This can helpprevent bending of catheter 28 (e.g., at the point it emerges from end56) and possible premature breakage of seal 26 during transport, storageand initial use.

Proximal-to-distal movement of cover 52 can also be constrained by asuitable stop—here, for example, a flange 57 at the proximal end ofcatheter 28 and/or distal end of vessel 20 sized larger than the innerdiameter passageway 54 at its proximal end 58 but smaller than the innerdiameter of that passageway at its distal end 56. As shown in thedrawing, the flange permits distal-to-proximal movement of the cover 52,but inhibits its proximal-to-distal movement.

In some embodiments of the invention, the cover 52, as well as the seals24, 26, are colored differently to alert and remind the user of theproper order in which they are to be broken. Those skilled in the artwill appreciate, of course, that coloration can be used in connectionwith other elements of the system 10, as well.

FIGS. 7A-7E depict use of cover 52—initially protecting, then,permitting manipulation (and breaking) of seal 26.

Initially, as shown in FIG. 7A, seals 24, 26 are unbroken andcompartment 20 a contains its post-manufacture complement of bufferagent 22 (and/or other gasses, fluids, solids). Consistent with thediscussion above, with the compartment 20 in this condition, the sizedifferential between outer diameter of vessel 20 and inner diameter ofpassageway 54 inhibits distal-to-proximal (e.g., “upward”) movement ofcover 52.

Referring to FIGS. 7B-7C, the cover 52 remains in its initial positionwhile the user breaks seal 24 (e.g., by bending the proximal end ofvessel 20 relative to port 18) and compresses vessel 20 in order toexpel buffer agent 22 for mixing with osmotic agent 14.

Referring to FIG. 7D, the user slides the cover in thedistal-to-proximal direction over the vessel 20 and away from the seal26, once the seal 24 has been broken and the outer diameter of vessel 20has been reduced (or, at least, resistance to such reduction has beeneliminated). With the cover 52 moved, the user can more readilymanipulate the distal end of vessel 20 and/or the proximal end ofcatheter 28 in order to break seal 26. See FIG. 7E.

Those skilled in the art will appreciate that cover 52 and/or vessel 20can have shapes other than those shown in FIGS. 6 and 7, yet, operate inthe manner discussed above in connection therewith.

One such alternate configuration is depicted in FIGS. 8A-8B, which showsin front- and side-views, respectively, a vessel 21 having the samefunction as element 20, above—albeit shaped with a central portion thatis elongate in the transverse direction and that generally defines anoval shape, as shown. The vessel 21 of the illustrated embodiment isformed from halves (or other portions) of PVC, polyolefin or othermedical-grade flexible or semi-rigid material that are glued,ultrasonically welded or otherwise fused along an edge 21A in theconventional manner known in the art (although the vessel can beformed—from a single portion or multiple portions—in other ways).

The cover 53 of FIGS. 8A-8B functions in the same manner as cover 52,above, albeit it includes a slot 53A that skirts the edge 21A when thecover 53 is slid in the distal-to-proximal direction over the vessel 21and away from the seal 26 (once the seal 24 has been broken and thevolume of vessel 21 has been reduced).

In comparison to the configuration of FIGS. 6-7, that shown in FIGS.8A-8B requires more complete reduction in outer diameter (via expulsionof a post-manufacture complement of solution 22 and/or other liquids,gasses or solids) from vessel 21 in order to permit distal-to-proximalmovement of cover 53.

FIGS. 11A-11F depict a configuration and use of vessel 21 to facilitateexpulsion of the post-manufacture complement of solution 22 (and/orother liquids, gasses or solids) into vessel 12 (not shown in thesedrawings) for mixing with solution 14 prior to introduction of theresulting solution into the patient's abdomen. Such expulsion isgraphically depicted in FIGS. 11C-11F by the arrow labeled 22. As withvessel 21 of FIGS. 8A-8B, vessel 21 of FIGS. 11A-11F serves a samefunction as vessel 20, described earlier, and may be used (e.g.,preferably, along with cover 53) in place of vessel 20 (or alternatestherefore, e.g., vessel 42, discussed elsewhere herein) in systemsaccording to the invention.

As above, the vessel 21 of FIGS. 11A-11F has a central portion that iselongate in the transverse direction and that generally defines an ovalshape. And, as above, it is formed from halves (or other portions) ofPVC, polyolefin or other medical-grade flexible or semi-rigid materialthat are glued, ultrasonically welded or otherwise fused along an edge21A in the conventional manner known in the art (although the vessel canbe formed—from a single portion or multiple portions—in other ways).

Preferably, the vessel 21 of FIGS. 11A-11F is formed to facilitatefolding of its halves 21B, 21C when the vessel is squeezed, e.g., by thepatient, health care provider or otherwise, following breakage of seal24. This is graphically depicted in steps 11B showing breaking of theseal 24 (as indicated by force arrows F_(B)), and 11C-11E showingfolding of the halves 21B, 21C when squeezed (as indicated by forcearrows F_(S)).

Such folding can be facilitated, by way of non-limiting example, bypre-creasing vessel 21 in a central region 21D, by reducing across-section of the vessel 21 in that region 21D, or otherwise. Indeed,in the illustrated embodiment, such folding is facilitated, at least inpart, by the proximal and distal ports of the vessel 21, the affixationof which in vicinity of region 21D provide an axis about which halves21B, 21C tend to naturally bend.

The cover 53 of FIGS. 11A-11F functions in the same manner as cover 53of FIGS. 8A-8B. Albeit, slot 53A of the cover of FIGS. 11A-11F ispositioned, sized and shaped to inhibit movement of the cover in adistal-to-proximal direction prior to breaking of seal 24 and expulsionfrom vessel 21 of a post-manufacture complement of PD buffer agentsolution 22 (and/or other liquids, gasses or solids). More particularly,the slot is positioned so that it (and, consequently, cover 53 itself)cannot be slid in the distal-to-proximal direction until both sides 21B,21C are aligned with the slot. Since only one such slot is provided inthe illustrated embodiment—generally, aligned normal to the plane of thevessel 21 (as shown in the drawings)—this necessitates squeezing thesides 21B, 21C together (in the manner of butterfly wings) or otherwisefolding the vessel 21 at least partially and, preferably, substantially.

Moreover, the slot 53A is sized and shaped to prevent such sliding untila cross-section of the region of sides 21B, 21C over which it (slot 53A)slides is reduced, i.e., via squeezing and expulsion of solution 22(and/or other liquids, gasses or solids) from vessel 21—preferably, byat least 10%-30% volumetrically and, still more preferably, at least30%-50% volumetrically and, yet still more preferably, at least 75%volumetrically and, yet, still more preferably, substantially all ofthat solution. This is graphically depicted in step 11F, showingrepositioning of the cover 53 via a sliding force, as indicated by arrowF_(L). As evident in the drawing, the cover 53 of the illustratedembodiment does not cover the entire vessel 21 when repositioned but,rather, only the central portion: the outer “wings” of sides 21B, 21Cremain outside. Of course, other embodiments may vary in this regard.

In some embodiments, slot 53A has rails, flats or other structures thateffect further squeezing of the halves 21B, 21C and consequent expulsionof solution 22 (and/or other liquids, gasses or solids) therefrom whenthat cover is slid in the distal-to-proximal direction over thosehalves.

The internal passageway of the cover 53 of FIGS. 11A-11F (likepassageway 54, discussed above) can be sized analogously to slot 53A,i.e., to inhibit movement of the cover in a distal-to-proximal directionprior to breaking of seal 24 and reduction in that an outer diameter ofa central region of vessel 21 via squeezing and expulsion of apost-manufacture complement of solution 22 (and/or other liquids, gassesor solids) from vessel 21. And, as discussed earlier, the internalpassageway of the cover 53 of FIGS. 11A-11F can have a larger innerdiameter at the distal end than at the proximal end, e.g., to helpprevent bending of catheter 28 and possible premature breakage of seal26. And, as above, proximal-to-distal movement of that cover 53 can beconstrained by a suitable stop and/or relative sizing of the innerdiameter of the internal passageway of the cover.

Of course, those skilled in the art will appreciate that the slot (orother opening) 53A and inner passageway of cover 53 of FIGS. 11A-11F canbe aligned, shaped and sized otherwise (and, indeed, that multiple slotscould be provided on cover 53A) in accord with the teachings hereof.

In some embodiments, the seal 24, the vessel 21, and the cover 53 arecolored differently to alert and remind the user of the proper order inwhich they are to be utilized. Thus, for example, the seal 24 can becolored red; the cover 53 can be colored white; and, the seal 26 can becolored blue. This red-white-blue combination can be effective inreminding patients or health care providers in locales where thosecolors have memorable significance (e.g., in the United States orFrance) that the seal 24 (red) is to be broken, first; the cover 53(white) is to be slid, next (after squeezing out the contents of vessel21); and, that the seal 26 (blue) is to be broken, last. Of course othercolor combinations or visual indica (e.g., lettering, numbering or othersymbology) may be used instead or in addition in other locales and/oramong other patients or health care provider.

Preferably, the vessel 21 of FIGS. 11A-11F is formed to facilitatefolding of its halves 21B, 21C when the vessel is squeezed, e.g., by thepatient, health care provider or otherwise, following breakage of seal24. This is graphically depicted in steps 11B showing breaking of theseal 24 (as indicated by force arrows F_(B)), and 11C-11E showingfolding of the halves 21B, 21C when squeezed (as indicated by forcearrows F_(S)).

Referring now to FIGS. 15 and 16A-16F, there is shown an alternatearrangement of the container system of FIGS. 1 and 11A-11F, here, withthe PD agent-containing compartments 12 a, 20 a formed in a singlevessel, e.g., a dual compartment bag or, more generally, a multi-chambervessel. Such a container system is advantageous, for example, insofar asit facilitates handling during manufacture and shipping, yet, affordsthe patient, health care provider or other user the other benefits ofthe systems described herein. An understanding of the embodiment ofFIGS. 15, 16A-16F may be appreciated by study of that drawing and thetext that follows in view of the discussion elsewhere herein. In thesedrawings, use of reference numerals like those referred to previously(or elsewhere herein) indicates like structure and functionality, albeitas adapted for use with the embodiment of that drawing.

The container 72 shown FIG. 15 includes two portions: one (labelled 12′)that embodies the overall structure and functionality of vessel 12 andthat includes compartment 12 a for PD osmotic agent solution 14; theother (labelled 21′), that embodies the overall structure andfunctionality of vessel 21 and that includes compartment 20 a for PDbuffer agent solution 22. In practice, vessels 12 and 21 as discussedabove can be fabricated separately and assembled together to form asingle vessel 72 (e.g., in a configuration as shown in FIG. 15) withcompartments 12 a, 20 a. Thus, for example, vessel 21 can be shaped witha central portion that is elongate in the transverse direction (orotherwise), as shown, and vessel 21 can be generally rectangular (orotherwise), as shown, with a “cut-out” to fit, mate with, or otherwiseaccommodate vessel 12, e.g., as shown. Preferably, however, vessel 72 isdirectly formed (e.g., from sheets or webs of PVC or other suitablematerial) to incorporate portions 12′ and 21′ and their respectivechambers 12 a and 20 a, as well as one or more of the additionalelements shown in the drawing and/or discussed below. Such fabricationis detailed in the sections that follow.

Illustrated vessel 72 can be fabricated from medical-grade PVC, e.g., inthe manner of a hanging “transfusion” bag, as illustrated, though it maybe of other configurations and/or comprised of other materials, such asflexible polyolefin or other medical-grade materials suitable used tocontain and/or administer peritoneal dialysis agents. The illustratedembodiment is sized for large capacity, e.g., delivery of 6 liters orabove of PD solution, though, it can be sized for standard clinical usecapacities (e.g., sized between 1-5 liters) as well. The compartments 12a, 20 a are proportioned as discussed above, i.e., such that compartment20 a is of small volumetric capacity in comparison to that compartment12 a. Thus, for example, where the first compartment 12 a of theillustrated embodiment is of a capacity sized between 1-5 (or 6) liters,the second compartment 20 a is sized about 5-50 ml (or 60 ml),preferably about 7.5-37.5 ml (or 45 ml). Thus, it will be appreciatedthat the ratio of volumetric capacity of the first to secondcompartments is about 20:1 to about 200:1, preferably about 50:1 toabout 150:1, and preferably, about 70:1 to about 140:1, and mostpreferably about 133:1. Of course, it will be appreciated that thevessel and its respective compartments 12 a, 20 a can be sized otherwisefor delivery of even larger and smaller amounts of PD solution.

The compartments 12 a, 20 a are coupled for fluid exchange via port 18(e.g., an aperture or tubing) that defines a fluid transfer path. In theembodiment of FIG. 15, the port 18 is disposed internally to one or moreof the compartments 12 a, 20 a—here, compartment 12 a, as shown. Theport 18 can be formed integrally with vessel 72 and/or one of itsconstituent portions 12′ and 21′. Alternatively, or in addition,coupling between that port and the vessel (and/or portions 12′, 21′) canbe provided via fusing, bonding, interference-fit, screw-fit or othercoupling mechanisms. As above, fluidic coupling between the compartments12 a, 20 a may be attained in other ways, e.g., by needle- orbayonet-like adapters affixed to either vessel (or its respective port)for receipt by the other vessel. Regardless, the port 18 (or otherfluidic coupling) can incorporate a diffuser 18A as discussed below,e.g., in connection with FIGS. 12A-12E.

Illustrated vessel 72 includes additional ports, as well. Thus, itincludes port 19, which can be used to transfer agents to and from thecompartment 12 a, e.g., during manufacture at the pharmaceutical plant,during mixing of the agents, and/or during administration of the mixedagents to the patient. It also includes port 27, disposed as shown, thatprovides a direct fluid outlet from chamber 20 a and that is coupled tocatheter 28 at a junction which is obscured in the drawing by cover 53.Such coupling can be provided by fusing, bonding, interference-fit,screw-fit or other mechanisms known in the art. Other embodiments mayuse a greater or fewer number of ports than those illustrated and,indeed, may use no ports at all (e.g., where needles or other methodsare used to add and remove agents from the compartment 12 a).

As above, a temporary seal 24 is provided in the fluid-transfer pathdefined by port 18. This prevents contact between or mixing of the PDosmotic agent and the PD buffer agent, e.g., until after sterilizationof the agents. Also as above (see, for example, FIGS. 11A-11F and theaccompanying text), a further temporary seal 26 (here, obscured by cover53) is provided in catheter 28 that leads, e.g., to the patient'speritoneal cavity (not shown), and prevents flow of PD solution, e.g.,until after mixing of the sterilized agents. The seals 24, 26 may beconstructed and fabricated as discussed above, for example, inconnection with FIGS. 1 and 5. In some embodiments, catheter 28 includesa connector for downstream apparatus, such as a PD tubing set, aperitoneal infusion port, or otherwise. One preferred such connector isthe Safe-Lock Connector™ commercially available from the assigneehereof. In embodiments utilizing that connector, or the like, the seal26 may comprise a frangible element integral thereto.

As with the embodiment discussed in connection with FIGS. 11A-11F.,cover 53 is slotted, and it slides from an initial (distal) position,wherein it protects seal 26 from manipulation, to a second (proximal)position, wherein it permits that seal to be broken. In the embodimentof FIG. 15, the slot 53A skirts over edge 21A of the portion 21′ thatforms the second chamber 20 a, when the cover 53 is slid in thedistal-to-proximal direction over that portion of vessel 72 and awayfrom the seal 26 (once the seal 24 has been broken and the volume ofvessel 21 has been reduced). Cover 53 and slot 53 a are sized andpositioned to require that a specified volume of solution 22 and/orother liquids, gasses or solids be expelled from cavity 20A and itsouter diameter be corresponding reduced in order to permitdistal-to-proximal movement of cover 53.

In this regard, portion 21′ of illustrated vessel 72 is formed tofacilitate folding of halves 21B, 21C of portion 21′ when it issqueezed, e.g., by the patient, health care provider or other user,following breakage of seal 24. This is graphically depicted in FIG. 16Bshowing breaking of the seal 24 (as indicated by force arrows FB), and16C-16E showing folding of the halves 21B, 21C when squeezed (asindicated by force arrows FS).

As above, such folding can be facilitated, by way of non-limitingexample, by pre-creasing portion 21′ in a central region 21D, byreducing a cross-section of the portion 21′ in that region 21D, orotherwise. Indeed, in the illustrated embodiment, such folding isfacilitated, at least in part, by the ports 18, 27, the affixation ofwhich in vicinity of region 21D provide an axis about which halves 21B,21C tend to naturally bend.

The cover 53 of the embodiment shown in FIGS. 15, 16A-16E functions inthe same manner as cover 53 of FIGS. 11A-11F. Thus, for example, slot53A of the cover of FIGS. 15, 16A-16E cannot be slid in thedistal-to-proximal direction until both sides 21B, 21C are aligned withthe slot. Since only one such slot is provided in the illustratedembodiment—generally, aligned normal to the plane of the portion 21′ (asshown in the drawings)—this necessitates squeezing the sides 21B, 21Ctogether (in the manner of butterfly wings) or otherwise folding thevessel 21 at least partially and, preferably, substantially.

As noted above, in some embodiments vessel 72 is directly fabricatedwith portions 12′ and 21′ and their respective chambers 12 a and 20 a.By way of example, the vessel 72 can be fabricated from two layers (or asingle folded layer) of PVC, flexible polyolefin or other suitable sheetor web material that is cut, formed and ultrasonically welded, glued orotherwise assembled to form a vessel of the configuration shown in FIGS.15 and 16A-16F. Ports 18 (including diffuser 18) and 27 can be fashionedsimultaneously and/or incorporated into the vessel during such assembly.

In the illustrated embodiment, the vessel 72 is fabricated such thatportions 12′ and 21′ are attached to one another (or substantially so)for purposes of manufacture and shipping, yet, can be partiallyseparated from one another, e.g., by the patient, health care provideror other use prior to mixing of the PD solution. Such partial separationpermits at least one of the compartments 12 a, 20 a and, preferably,compartment 20 a, to be manipulated, e.g., bent, twisted, squeezedand/or folded, at least partially independently of the other compartment12 a, e.g., in the manner shown in FIGS. 16B-16F. Thus, for example, asshown in those drawings, portion 21′ can be separated from portion 12′so that, for example, it can be squeezed, folded and the contents 22 ofits respective compartment 20 a expelled into compartment 12 a withoutsubstantially folding portion 12′ and squeezing its respectivecompartment 12 a.

To this end, during fabrication of vessel 72, the PVC, flexiblepolyolefin or other fabrication material is perforated in one or moreregions 74 between the portions 12′, 21. Prior to use, thoseperforations can be torn by the patient, health care provider topartially separate those portions from one another—and, morespecifically, for example, to permit separation of the type shown inFIGS. 16B-16F—and to facilitate independent manipulation of theirrespective compartments as also shown there. In lieu of (or addition to)perforations, the portions can be cut (or otherwise separated) from oneanother in the region(s) 74 and tacked ultrasonically, or otherwise, tolike affect. By leaving the perforations or tack-welds unbroken untiluse, processing and handling of the vessel 72 is facilitate duringmanufacture and shipping.

FIGS. 12A-12E depict a container system 10 in which port 18 of vessel 12includes a diffuser 18A for facilitating mixing of solution 22 (and/orother liquids, gasses or solids of vessel 21) with solution 14 (ofvessel 12). The diffuser 18A is shown in use with a system 10 thatincludes a vessel 12 of the type shown in FIGS. 1, 3, 4, 6, 9, and avessel 21 and cover 53 of the types disclosed in FIGS. 11A-11F; however,it will be appreciated that it the diffuser 18A can be utilized inconnection with the other vessels and/or configurations shown and/ordiscussed herein.

Referring to FIG. 12A, the diffuser 18A of the illustrated embodimentcomprises a cap—here, of a generally elongated shape, but of othershapes in other embodiments—having a proximal end that is disposedwithin compartment 12A and that includes multiple inlet/outlet apertures18B. A distal end of the diffuser cap is coupled to and/or comprisestubing (or other structure) defining port 18, which, as noted above,provides for fluid coupling between the vessels 12 and 21.

Three such apertures 18B are shown on the proximal end of theillustrated diffuser 18A, though, other pluralities of apertures may beused in other embodiments, e.g., two apertures, four apertures, fiveapertures, and so forth. And, while apertures 18B are disposed in theillustrated embodiment at the tip of the proximal end of the diffuser18A, in other embodiments they may be disposed elsewhere on diffuser 18Ain fluid communication with compartment 12A

Illustrated apertures 18B are in fluid communication with an internalchannel 18C that extends to the distal end of diffuser 18A and thatsupports fluid coupling between vessels 12, 21, as shown. In theillustrated embodiment, two of the three apertures 18B extend from thechannel 18C at an angle Ω, while one of the apertures is in line withthe channel 18C, all as shown. As a result, diffuser 18A of theillustrated embodiment causes solution 22 that is expelled into vessel12 to disperse with an angular dispersion of 2Ω into solution 14, thoughthe diffuser of other embodiments may effect other angular dispersions.

The angle Ω of the illustrated embodiment is in the range 20°-70° (witha resulting angular dispersion 2Ω in the range 40°-140°) and, morepreferably 30°-60° (with a resulting angular dispersion 2Ω in the range60°-120°) and, still more preferably, about 25° (with a resultingangular dispersion 2Ω of about 50°), as shown. In other embodiments,other angular ranges may be used depending on the location of theproximal tip of diffuser 18A within compartment 12A, the size of thatcompartment, the characteristics of the fluids being mixed, and soforth. Although the apertures are disposed symmetrically about an axisin the illustrated embodiment, other embodiments may forego suchsymmetry.

Diffuser 18A may comprises nylon, plastic, or other medical-gradematerial (and, preferably, such medical materials as do not fuse to PVCduring heat sterilization). In the illustrated embodiment, diffuser 18Ais fabricated from polycarbonate and is the same material as used infrangible members (e.g., 62, 64) discussed elsewhere herein. In otherembodiments, diffuser 18A is fabricated from polyvinylchloride (PVC) andis the same material as used for the catheter 28 and other ports and/ortubing that comprise system 10. The apertures 18C of the illustratedembodiment are preferably 1.0 to 1.5 mm in diameter, though otherembodiments may use apertures of different and/or varying sizes, e.g.,depending on the characteristics of the fluids being mixed and otherfactors indicated above, all by way of example.

Diffuser 18A facilitates mixing of solution 22 (and/or other liquids,gasses or solids in vessel 21) with solution 14 when the patient orhealth care provider squeezes vessel 21 in the manner shown in FIGS.11C-11F. This is graphically depicted in steps 12B-12D showing expulsionof fluid 22 (as indicated by arrows 22) when container 21 is squeezed(as indicated by force arrows F_(S)) and cover 53 is slid (as indicatedby force arrow F_(L)).

Diffuser 18A further facilitates mixing of those solutions, followingbreakage of seal 26, when the combined PD solution is expelled into thecatheter 28 (and any downstream equipment) for introduction to apatient. This is graphically depicted in step 12E showing expulsion(e.g., under the force of gravity and/or manipulation of vessel 12) ofthe combined solutions 14, 22 from the vessels 12 and 21, and exit viathe catheter 28 (all as indicated by the unlabelled arrows).

The configurations shown in FIGS. 11A-11F and 12A-12E may be used inconnection with the PD osmotic agents, PD buffer solutions and other PDcomponents discussed below. In this regard, it will be appreciated that,consistent with the remarks above, vessel 21 may be used (e.g., alongwith cover 53 or alternates therefor) in place of vessel 20 (oralternates therefor, e.g., vessel 42) discussed below and elsewhereherein.

Advantages of the configurations shown in FIGS. 11A-11F and 12A-12Einclude that they permit the solutions 14 and 22 to be more readilycombined following expulsion of solution 22 into vessel 12, e.g.,necessitating limited manipulation by the patient or health careprovider in order to assure an acceptable mix of PD solution that lackspH extremes and is an appropriate range for introduction to the patient.In this regard, for example, the diffuser 18A facilitates mixing PDsolutions of different densities and/or viscosities—and, particularly,by way of non-limiting example, a PD buffer solution 22 that has densityand/or viscosity greater than that of the PD osmotic agent 14—to bemixed quickly and homogeneously, with minimal effort. An advantage ofthe vessel 21 of FIG. 11A is that squeezable folding of its sides 21B,21C (as detailed above) increases infusion pressure of solution 22 forbetter mixing in vessel 12. It also better increases chances forcomplete infusion of solution 22.

In this context a procedure for use of system 10 as shown in FIGS.12A-12E is shown in FIGS. 13A-13F. The system of FIGS. 13A-13F,additionally includes a drain bag 23, which can be supplied with thesystem 10 for use in draining spent PD solution from the patient.

Referring to FIG. 13A, prior to use of the system 10, the patient orhealth care provider inspects and familiarizes himself/herself withvessels 12, 21, seals 24, 26 and cover 53.

Referring to FIG. 13B, the patient or health care provider next breaksthe seal 24 (which, as noted above, can be differentially colored red orotherwise in some embodiments) and, then, folds the vessel 21 in half,squeezing firmly until the solution 22 originally contained in thevessel 21 is expelled into solution 14 of vessel 12.

Referring to FIG. 13C, the patient or health care provider next presseson vessel 12 in order to push solution back into vessel 21. In someembodiments, the steps shown in FIGS. 13B and 13C are carried out threetimes to facilitate thoroughly “washing” solution 22 from vessel 21.

Referring to FIG. 13D, the patient or health care provider next invertsthe system 10 (and, significantly, vessel 12) to facilitate still morethorough mixing of the solutions 22, 44. In some embodiments, the stepshown in FIG. 13D is carried out three times to facilitate thoroughmixing of the solutions 14, 22.

Referring to FIG. 13E, the patient or health care provider next foldsvessel 21 in half and slides the cover 53 (which, as noted above, can bedifferentially colored white or otherwise in some embodiments) up overthe central portion of the vessel 21 until the seal 26 (which, as notedabove, can be differentially colored blue or otherwise in someembodiments) is exposed where the tubing comprising catheter 28 isattached.

Referring to FIG. 13F, the patient or health care provider next gripsthe cover 53 (which is now repositioned over at least a portion ofvessel 21) and grips the seal 26 with the other hand and bends to breakthe seal 26, thereby, opening a fluid pathway for outflow of thecombined solutions 14, 22 (e.g., under gravity feed as effected byhanging system 10 and, significantly, vessel 12 vertically) via catheter28 to the patient.

Of course, it will be appreciated that system 10 of FIGS. 12A-12E, aswell of the other systems described herein, may be utilized withprocedures other than those in FIGS. 13A-13F, as discussed more fullybelow. FIGS. 14A-14F are graphs depicting pH as a function of time ofthe outflow of catheter 28 for such alternate procedures for samplesystem(s) of the type shown in FIGS. 12A-12E when used with normallyexpected operating procedures (e.g., by way of non-limiting example,where vessel 21 is squeezed with at least a nominal squeezing forcesufficient to achieve a fluid pressure of about 8 psi).

By way of non-limiting example, in one preferred such alternateprocedure the steps shown in FIGS. 13B and 13C are carried out two times(rather than three times), and the step shown in FIG. 13D is carried outone time (rather than two times). A graph of pH as a function of time ofthe outflow volume of catheter 28 for sample system(s) of 5 L capacityof the type shown in FIGS. 12A-12E using this procedure is presented inFIG. 14A. In the sample system(s), the initial solution 14 in vessel 12comprised dextrose, calcium chloride, magnesium chloride, and sodiumchloride at pH 2.6-3.2, while the initial solution 22 in vessel 21comprised sodium lactate and sodium bicarbonate at pH 9.2-9.4. By way offurther non-limiting example, in another such alternate procedure thesteps shown in FIGS. 13B and 13C were carried out two times with onlynominal squeezing forces exerted on the vessel 21; inverting step shownin FIG. 13D was not carried out. A graph of pH as a function of theoutflow volume of catheter 28 for sample system(s) of 5 L capacity ofthe type shown in FIGS. 12A-12E using this procedure, with a nominalsqueezing force of about 8 psi, is presented in FIG. 14B; that for anominal squeezing force of about 15 psi is presented in FIG. 14C. Thesample system(s) were as describe in the preceding example.

By way of further non-limiting example, in another such alternateprocedure the step shown in FIG. 13B was carried out one time withnominal squeezing forces exerted on vessel 21; the step shown in FIG.13C was not carried out; and, the inverting step shown in FIG. 13D wasnot carried out. A graph of pH as a function of time of the outflowvolume of catheter 28 for sample system(s) of 5 L capacity of the typeshown in FIGS. 12A-12E using this procedure is presented in FIG. 14D.The sample system(s) were as describe in the preceding example.

By way of further non-limiting example, in another such alternateprocedure the step shown in FIG. 13B was carried out one time with lowpressure exerted on vessel 21; the step shown in FIG. 13C was notcarried out; and, the inverting step shown in FIG. 13D was carried outone time. A graph of pH as a function of the outflow volume of catheter28 for sample system(s) of 5 L capacity of the type shown in FIGS.12A-12E prepared using this procedure is presented in FIG. 14E. Thesample system(s) were as describe in the preceding example.

Referring to FIG. 9, an alternate arrangement of the structures shown inFIG. 1 can further insure that the seals are broken in an order thatprevents fluid transfer to the catheter 28 (and any downstreamequipment) prior to mixing of the PD agents. That drawing depictscontainer system 60 of the same general configuration as containersystem 10 of FIG. 1 (as indicated by like reference numerals), albeitwith the second seal (element 26 of FIG. 1, element 62 of FIG. 9)disposed within vessel 20 (e.g., rather than between the distal port ofthat vessel 20 and the catheter 28) so as to inhibit its manipulationand breaking until seal 24 is broken and fluid (or other) pressurewithin the vessel is reduced.

As with seal 26, seal 62 is a frangible member that can be fabricatedfrom nylon, plastic, or other medical-grade material, and that can beformed in the configurations discussed above in connection with seal 24(and shown, for example, in FIG. 5). Moreover, like seal 26, seal 62 canbe disposed between the distal port of the vessel 20 and the catheter 28and affixed to (and/or formed integrally with) an interiorfluid-transfer path of one or both of those.

Preferably, however, seal 62 is disposed so as to inhibit it from beingmanipulated (and, more significantly, broken) when vessel 20 containsits post-manufacture complement of PD buffer agent solution 22 (and/orother liquids, gasses or solids). In the embodiment of FIG. 9, this isachieved by extending the seal 62 within the vessel 20, e.g., in themanner shown in FIG. 9, so as to inhibit squeezing, twisting or othermanipulation of vessel 20, catheter 28 or otherwise from breaking seal62 prior to breaking of seal 24 and (i) expulsion of at least some ofits post-manufacturing complement of PD buffering agent 22 (and/or otherliquids, gasses or solids)—and, preferably, expulsion of at least10%-30% and, still more preferably, at least 30%-50% and, yet still morepreferably, at least 50%—of such agent (and/or other liquids, gasses orsolids) and/or (ii) reduction of the turgidity or other pressureeffected within the vessel 20 by that agent 22 (and/or other liquids,gasses or solids). Those skilled in the art will appreciate thatconfigurations of seal 62 other than that shown in FIG. 9 can beemployed to this same end, as well.

In some embodiments of the invention, the seals 24, 62, are coloreddifferently to alert and remind the user of the proper order in whichthey are to be broken. Those skilled in the art will appreciate, ofcourse, that coloration can be used in connection with other elements ofthe system 10, as well.

FIGS. 10A-10D depict utilization of PD system 60, including seal 62, ina manner according to the invention.

Initially, as shown in FIG. 10A, seals 24, 26 are unbroken andcompartment 20 a contains its post-manufacture complement of bufferagent 22 (and/or other gasses, fluids, solids). Consistent with thediscussion above, vessel 20 is under sufficient fluid (or other)pressure to inhibit squeezing, twisting or other manipulation of itsufficient to break seal 62.

Referring to FIGS. 10B-10C, seal 62 remains intact while the user breaksseal 24 (e.g., by bending the proximal end of vessel 20 relative to port18) and compresses vessel 20 in order to expel buffer agent 22 formixing with osmotic agent 14.

Referring to FIG. 10D, the user bends or otherwise manipulates vessel 20in order to break seal 62, once the seal 24 has been broken and thepressure within vessel 20 has been reduced. Once that seal 62 is broken,the mixed PD constituents can pass to catheter 28 (and/or otherdownstream equipment).

Systems as described above (and below) can be used to contain, mix anddispense a variety of constitutes. In one embodiment, the firstcompartment houses a PD osmotic agent at physiological useconcentrations, i.e., substantially at concentrations at which thatagent will be introduced into the patient's abdomen. Thoseconcentrations for example of dextrose is about 1.5%-4.25%, morepreferably, about 2.0%-4.0% and, still more preferably, about 2.0%-3.0%.The PD osmotic agent is also at a physiologically low pH, i.e., a pHbelow that at which that agent will be introduced into the patient'sabdomen, preferably, the pH is about 1.0-6.0 and, most preferably, about1.0-3.0.

Examples of suitable PD osmotic agents include, but are not limited to,sugars such as glucose (e.g., dextrose), poly(glucose) (i.e., a polymermade from repeating glucose residues, e.g., icodextrin, made fromrepeating dextrose units), fructose, dextrans, polyanions, and the like.Other PD osmotic agents may be non-sugar osmotic agent that function asan equivalent could be a viable substitute, such as small amino acids.

In a preferred example, the PD osmotic agent is dextrose. Theconcentration of dextrose is about 1.5%-4.25%, more preferably, about2.0%-4.0% and, still more preferably, about 2.0%-3.0%.

As used herein, “mEq/L” refers to the concentration of a particular PDsolution component (solute) present in proportion to the amount of waterpresent. More specifically, mEq/L refers to the number ofmilli-equivalents of solute per liter of water. Milli-equivalents perliter are calculated by multiplying the moles per liter of solute by thenumber of charged species (groups) per molecule of solute, which is thenmultiplied by a factor of 1,000. As an example, when 10 grams of citricacid are added to a liter of water, the citric acid is present at aconcentration of 10 g/L. Anhydrous citric acid has a molecular weight of192.12 g/mol; therefore, the number of moles per liter of citric acid,and consequently citrate anion (since there is one mole of citrate anionper mole of citric acid), is 10 g/L divided by 192.12 g/mol, which is0.05 mol/L. Citrate anion has three negatively charged species in theform of carboxylate groups. Accordingly, the citrate concentration of0.05 mol/L is multiplied by three and then by 1,000, in order to providea concentration of citrate in terms of mEq/L, which in the presentexample is 156 mEq/L of citrate anion.

The same method of calculation can be used to determine the mEq/L ofother agents such as lactate and dextrose. For example, 4.48 grams ofsodium lactate (molecular weight of 112.1 gram/mol) per liter of waterprovides 40 mEq/L of sodium cations and 40 mEq/L of lactate anions. Fordextrose, 42.5 grams of dextrose (molecular weight of 180.2 gram/mol)per liter of water provides 235.8 mEq/L of dextrose.

The PD osmotic agent can contain electrolytes, in addition to theosmotic agent. Suitable electrolytes may include, for example, sodium,potassium, calcium and magnesium. In the PD solution composition, thepreferred concentration range for sodium is from about 100 to about 132mEq/L. The preferred concentration range for potassium is less thanabout 3.50 mEq/L. The preferred concentration range for calcium is lessthan about 2.50 mEq/L. The preferred concentration range for magnesiumis less than about 1.50 mEq/L.

The solution in the second container can be a concentrated agent and,specifically, in the illustrated embodiment (for example), aconcentrated PD buffer solution. The term “concentrated” as used hereinrefers to an agent that is stronger than the chemically “Normal”concentration for that particular agent. The terms “Normal” and “Normalconcentration” are used herein in the conventional sense of the chemicalarts to refer to solutions having a concentration of 1 gram equivalentper liter of a solute. Thus, the Normal concentration of an ionic bufferagent is effectively equal to the molar concentration divided by thevalence (the number of free or missing electrons) of the ion. Forexample, if a standard amount of a buffer agent is 60% (w/w), then 60mls of that buffer agent would be added to one liter of water in orderto obtain Normal concentration for that agent. In order to achieve a10-fold increase in concentration (e.g., as in some embodiments of theinvention), only 6 mls of the buffer is needed in one liter of solution.

The concentrated agent and, more specifically, the concentrated bufferutilized in systems and methods according to the invention can be of anyconcentration that is stronger than the chemically Normal concentration.For example, the concentrated buffer can be about 3-fold higher thanNormal, 5-fold, 7-fold, 10-fold, 15-fold, and up to at least 50-foldhigher than the Normal buffer. As those skilled in the art willappreciate, conventional, commercially available PD solutions, such asDeflex, by way of non-limiting example, are of chemically “Normal”concentration. Thus, the concentrated PD buffer agents utilized inembodiments of the present invention are of manifold increases inconcentration relative to the commercial norm. The advantage of usingconcentrated buffers is that they can be stored and sterilized in smallvolume containers.

Alternatively, a sufficient quantity of buffer to produce a Normalconcentration of a buffer upon mixing can be stored in a reduced volume.For example, a Normal amount of lactate buffer is typically 60% (w/w),i.e., 7.46 grams of sodium lactate buffer to one liter of solution. Inthis invention, the lactate buffer can be contained in the vessel 20such that 7.46 grams of sodium lactate is contained in a vessel with avolumetric capacity of about 15 mls. The advantage of the invention isthat the buffers can be contained and sterilized in small volumecontainers.

Examples of buffers include, but are not limited to, lactates, acetates,pyruvates, citrates, and the like. The lactate source may be any oflactic acid, sodium lactate, potassium lactate, calcium lactate,magnesium lactate, and the like. The acetate source may be any of aceticacid, sodium acetate, potassium acetate, calcium acetate, calciumacetate, magnesium acetate, and the like. Any or all of these chemicalsare commercially available, in USP-grade if desired, from many chemicalsupply houses including, for example, Aldrich Chemical Co., MilwaukeeWis.

A preferred example of a PD buffer solution is a concentrated lactatebuffer solution comprising lactate at a concentration of 20milliequivalent per liter (mEq/l) to about 60 mEq/l, preferably aconcentration of about 30 mEq/l to about 50 mEq/l, and most preferably,a concentration of 40 mEq/l. In addition, the lactate buffer solutionmay further comprise a bicarbonate at a concentration of about 5 mEq/lto about 10 mEq/l. A preferred buffer comprises 30-35 mEq/L of sodiumlactate and 10-5.0 mEq/L of sodium bicarbonate.

The pH range of the PD osmotic agent solution is about 1.0-6.0 and, mostpreferably, between 1.0-3.0. The pH range of the PD buffer agentsolution is about 8.0 to about 14.0, and, more preferably, a pH of about9.0 to about 12 and, still more preferably, a pH of about 9.0 to about10.0.

The different PD components can be dissolved in water that isessentially pyrogen-free and that at least meets the purity requirementsestablished by United States Pharmacopia (USP)-grade for PD solutions.

A Normal PD solution typically comprises dextrose, sodium chloride,magnesium chloride and calcium chloride, sodium lactate, sodiumhydroxide or hydrochloric acid added to adjust pH levels. The resultingpH of Normal PD solutions is about pH 5.0-6.0, which is less thanoptimum for blood, which has a pH of about 7.35 and 7.45. The Normal PDsolutions often also contain GDPs. The seven commonly identified andpublished GDPs are acetaldehyde (AcA), 3-deoxglucosone (3-DG),5-hydroxymethylfuraldehyde (5-HMF), glyoxal (Glx), methglyoxal (M-Glx),formaldehyde (FoA), and furaldehyde (FurA).

The systems and methods of the present invention provide PD solutionswith reduced GDPs, as well as with more physiologically optimalconcentrations and pH's. To this end, the PD osmotic agent solution andPD buffer agent are sterilized separately, thus, reducing the formationof degradation products that would otherwise result from the reaction ofthose agents at sterilization (or other high temperatures). The pH ofthe separate solutions is adjusted, moreover, in the illustratedembodiment, to further minimize GDP production during sterilization.That is to say the pH range of the PD osmotic agent solution is about1.0-6.0 and, more preferably, between 1.0-3.0, while the pH range of thePD buffer agent solution is about 8.0 to about 14.0, and, morepreferably, a pH of about 9.0 to about 12 and, still more preferably, apH of about 9.0 to about 10.0. After sterilization, the buffer agent canbe added to the osmotic agent solution, producing a mixed PD solutionwith a pH in the physiologically optimal range of about 5.0 to about 8.0and, more preferably, about 6.0 to about 7.0, and, most preferably,about pH 7.2. As a result, systems and methods as described herein canprovide PD solutions with an overall reduction in GDPs in the range ofabout 50% to about 80% compared with Normal PD solutions.

With continued reference to the drawings, in order to keep the PDosmotic and buffer agents separate prior to sterilization, vessels 12and 20 are manufactured, shipped and stored with seals 24 and 26 intact.Those containers may be pre-assembled, e.g., so that they are availablefor use by a patient, health care provider or manufacturer in theconfiguration shown in FIG. 1 (not including attachment of catheter 28),or they may be manufactured, shipped and stored as kits, e.g., with thevessels 12 and 20 filled with their respective PD agents, but inunassembled form. The seal 24 may also be broken after sterilization atthe time of manufacture.

Regardless, the vessels 12, 20 are sterilized before the seal 24 isbroken and, therefore, before their respective contents have had achance to mix. This is shown in step 30 of FIG. 2, which is a flow chartdepicting a sequence for sterilizing and administering a PD solutionaccording to the invention. This sterilization, which can be performedby the manufacturer and/or the health care provider, is achieved bysteam-sterilization or other such conventional methods known in the art.Sterilization times and temperatures/pressures are in accord with thoseappropriate for the separated agents contained in vessels 12, 20, notreduced times and temperatures/pressures which might otherwise benecessary to prevent GDP build-up in sterilization of the combinedcomponents.

With continued reference to FIG. 2, step 32, following sterilization,seal 24 is broken (e.g., by squeezing and/or twisting of vessel 20and/or port 18) to permit mixing of the PD buffer agent with the PDosmotic agent. The agents can be mixed by shaking, kneading or otheraction on the vessels 12, 20. See step 34. Thereafter, the solution isready for administration—pending, for example, warming or other stepsnecessary for patient comfort or well being. To this end, seal 26 isbroken, e.g., by squeezing or twisting of the distal port of vessel 20and/or its interface with catheter 28. See step 36. Where a protectivemember (such as cover 52) is present, step 36 can further include thestep of moving the protective member to allow access to, and breakingof, seal 26. Once seal 26 is broken, the PD solution can exit from theport into the catheter (and any downstream equipment) and, finally, to apatient. See step 38.

FIG. 3 depicts system 40 according to a further embodiment of theinvention generally constructed and utilized (as indicated by likereference numerals) as system 10, described above. Differences inconstruction and utilization are discussed in the text that follows andare evident in the drawings.

Vessel 42 of system 40 comprises compartment 42 a for, by way ofexample, PD buffer agent solution 22, as generally described above.Compartment 42 a and vessel 42 are collapsible—i.e., they are configuredsuch that force applied thereto, e.g., by a patient, health careprovider or other, causes the volume of compartment 42 a to at leasttemporarily decrease so as to expel fluid contained therein. To thisend, in the illustrated embodiment, vessel 42 has fan-fold walls, orbellows, along an axis aligned with a direction of fluid expulsion—here,along the fluid transfer path between vessel 42 and vessel 12. Otherembodiments may utilize walls of other construction to facilitatecollapse along the same or other axes. Regardless, those walls arepreferably sufficiently durable to prevent leakage, e.g., so that afterfluid expulsion, the compartment 42 a can form part of a fluid transferpath between the compartment 12 a and the patient's peritoneal cavity.

Illustrated vessel 42 may be fabricated from PVC, polyolefin,polypropylene, rubber and/or other medical grade materials suitable forforming a collapsible container as described herein. As with vessel 20(FIG. 1), above, vessel 42 can be formed, e.g., by blow molding,dip-forming, or otherwise.

As above, seal 24 is adapted to prevent fluid transfer (or othercontact) between the PD agents contained in the compartments duringmanufacture, transport, storage and sterilization of system 40, yet, topermit such fluid transfer upon squeezing, twisting or othermanipulation of vessel 42 and/or port 18 by a patient, health careprovider, or manufacturer, e.g., following sterilization.

Like seal 26 of systems 10 and 50 (FIGS. 1 and 6), seal 44 of system 40is adapted to prevent fluid transfer to the catheter 28 (and anydownstream equipment) prior to sterilization and mixing of the PDagents. However, unlike seal 26, seal 44 (which, too, is disposed at thedistal port of the vessel 42) is broken by a further member 46 that isdisposed in compartment 42 a and that pierces, cuts or otherwise breaksseal 44 when the vessel 42 and compartment 42 a have been compressedsufficiently to insure expulsion of the fluid 22 into compartment 12 a.

Seal 44 can be formed of PVC, polyolefin, polypropylene, rubber and/orother medical grade materials suitable for preventing fluid transfer,e.g., during manufacture, shipping, storage, sterilization, butsusceptible to being broken, e.g., by member 46 as described here,following sterilization and mixing of the agents 14, 22.

In the illustrated embodiment, member 46 is depicted as a bayonet,though in other embodiments it may be of another shape. It can beconstructed of the same materials utilized, e.g., for element 24. Member46 can be formed near the proximal port of vessel 42 (e.g., oppositeseal 24) and affixed to (and/or formed integrally with) an interiorfluid-transfer path between the vessels, as shown, though in otherembodiments it may be disposed elsewhere, e.g., preferably so that itbreaks member 44 upon sufficient compression of vessel 42 andcompartment 42 a. To this end, in the illustration, member 46 is of suchlength that its tip (for piercing seal 44) is disposed approximately 40%from the proximal end of compartment 42 a. In other embodiments, themember may be of other lengths, depending upon the compressibility ofcompartment 42 a and on the desired degree of expulsion of fluid 22 fromcompartment 42 a to compartment 12 a prior to piercing of seal 44.

As above, the container system 40 permits the PD osmotic agent solutionand PD buffer agent to be sterilized separately, thus, reducing theformation of degradation products that would otherwise result from thereaction of the osmotic agent with the buffer agent at high temperature.To this end, the vessels 12 and 42 are manufactured, shipped and storedwith seals 24 and 44 intact. Those containers may be pre-assembled,e.g., so that they are available for use by a patient or health careprovider in the configuration shown in FIG. 3 (not including attachmentof catheter 28), or they may be manufactured, shipped and stored askits, e.g., with the vessels 12 and 42 filled with their respective PDagents, but in unassembled form. As noted above, the seal 24 may also bebroken after sterilization at the time of manufacture.

Regardless, as above, the vessels 12, 42 are sterilized before the seal24 is broken and, therefore, before their respective contents have had achance to mix. Such sterilization may be accomplished as describedabove, e.g., in connection with step 30 of FIG. 2.

Following sterilization, a factory worker, health care provider, apatient, or other, breaks seal 24 (e.g., by squeezing and/or twisting ofvessel 42 and/or port 18); see, FIG. 4A. He or she then compresses (orcollapses) vessel 42 to expel agent 22 from compartment 42 a intocompartment 12 a, thereby, facilitating its mixing with agent 14; see,FIG. 4B.

The factory worker, health care provider, patient or other continuescompressing (or collapsing) vessel 42 until the tip of member 46contacts and breaks seal 44; see, FIG. 4C. This allows the PD solutionto exit from the port into the catheter (and any downstream equipment)and, finally, to a patient.

It will be appreciated that systems and methods according to theinvention are applicable to a range of peritoneal dialysis applicationsand other medical applications in which at least one agent (orcombination of agents) requires separate sterilization prior tocombination with another agent (or combination thereof). According toconventional practice, such agents are sometimes combined prior tosterilization or, if combined after sterilization, for example, byinjecting one of them into a medication port of a container that holdsthe other agent. The former increases risk of degradation of the agents.The latter increases the risk to health care personnel and/or thepatient. Systems and methods of the invention avoid these risks andother shortcomings of the prior art by allowing the agent(s) to besterilized separately and, then, combined, e.g., without the use ofneedles or other mechanisms that are expensive, unwieldy, and/or placethe agent(s), health care personnel and/or patients at risk.

Another advantage of systems and methods of the invention, is thatdepending on the requirements of the agent that will be added to themedical solution, the second vessel can be coated with materials thatmaintain the shelf life and/or stability of the agent or additive.Examples of additives that can be administered with this invention areamino acids, proteins, heparin, and vitamins.

As evident in the examples below, systems and method of the inventionhave been used to prepare PD solutions with reduced GDPs and a morephysiologically optimal pH levels.

TABLE 1 Samples Preparation pH mL of 1.0 M Adjusted HCI per Liter LabelTo of Solution WFI Glucose CaCl₂*2H₂O MgCl₂*2H₂O NaCl 1 3.0 1.37 80 L3,400 g 14.72 g 4.072 g 430.16 g 2 4.0 0.37 3 4.5 0.27 4 5.2 0.18 BufferStraight Lactate Syrup up to 1000 g in a 1-Liter Bag

Table 1 shows sample preparations with the PD solutions constituents atdifferent pH values. The sample labeled “Buffer” has concentratedlactate buffer solution added to it.

Table 2 shows the results of HPLC analysis of the samples to examine thevarious degradation products. The seven degradation products that wereanalyzed are as follows: acetaldehyde (AcA), 3-deoxglucosone (3-DG),5-hydroxymethylfuraldehyde (5-HMF), glyoxal (Gix), methglyoxal (M-Gix),formaldehyde (FoA), and furaldehyde (FurA). The data from Table 2 showsthat GDPs formation around pH 3.0 is the lowest among the solutionsprepared and the Normal/commercial products. Sodium lactate as a bufferagent in PD solutions results in acetaldehyde (AcA) formation (Seecolumn entitled “pH” in Table 2). The results also demonstrate theeffectiveness of reducing AcA formation by separating sodium lactatefrom the rest of the PD solution for steam sterilization. By addingsodium lactate buffer solution to the main PD solution at pH 3.0 (group1), the resulting mixed PD solution has a pH of 5.2, which is the sameas Normal PD solutions (referred to as “Delflex” in Table 2), but withsignificantly reduced GDPs than Normal PD solutions. This datademonstrates that reduced GDPs are obtained under current formulationand pH levels using the system of the invention. The data also showsthat PD formulations with reduced GDPs are obtained at a physiologicalof around pH 7.0 (Table 4). Thus, the systems and methods of theinvention provide significantly reduce GDPs in PD solutions that containdextrose as an osmotic agent and sodium lactate as buffer.

TABLE 2 GDPs results from HPLC Analysis Cl 3-DG AcA 5-HMF Gix M-Gix FoAFurA Label pH (mEq/L) (μmol/L) (μmol/L) (μmol/L) (μmol/L) (μmol/L)(μmol/L) (μmol/L) Buffer 8.1 — ND 15 ND ND ND 3 ND 1-A 3.0 — 37 ND ND ND7 ND ND 1-B 3.0 — 119 ND 18 ND 8 ND ND 1-C 3.0 — 115 2 23 ND 7 ND ND 1-D3.0 — 119 1 22 ND 9 ND ND 2-A 4.0 — 65 ND ND ND 9 ND ND 2-B 4.0 — 299 ND39 ND 8 1 ND 2-C 4.0 — 299 ND 38 ND 13 ND ND 2-D 4.0 — 248 ND 34 0.2 8ND ND 3-A 4.7 — 91 ND ND ND 9 ND ND 3-B 4.4 — 526 0.1 45 0.5 9 ND ND 3-C4.4 — 532 ND 46 ND 9 ND ND 3-D 4.4 — 513 ND 46 0.7 14 ND ND 4-A 5.5 —112 ND ND 0.2 7 ND ND 4-B 4.5 — 699 ND 54 0.7 8 ND ND 4-C 4.5 — 653 ND51 1.6 11 ND ND 4-D 4.5 — 649 0.2 44 0.6 8 3 ND 1-A (buffered) 5.3 95.545 6 ND ND 9 ND ND 1-B (buffered) 5.3 95.6 131 16 26 ND 8 ND ND 1-C(buffered) 5.3 94.8 128 15 25 ND 9 ND ND 1-D (buffered) 5.3 95.4 134 1525 ND 10 ND ND 2-A (buffered) 6.1 95.7 90 6 ND ND 10 ND ND 2-B(buffered) 6.1 95.2 316 20 39 ND 7 ND ND 2-C (buffered) 6.1 95.3 307 1940 ND 11 ND ND 2-D (buffered) 6.1 95.0 303 2 35 ND 9 ND ND 3-A(buffered) 6.4 95.1 95 10 ND 0.5 11 ND ND 3-B (buffered) 6.3 95.3 570 1846 0.3 7 ND ND 3-C (buffered) 6.3 95.1 537 3 45 0.5 13 ND ND 3-D(buffered) 6.3 95.4 560 20 45 ND 7 ND ND 4-A (buffered) 6.6 95.4 121 7ND 0.4 10 ND ND 4-B (buffered) 6.3 95.0 650 16 52 ND 9 ND ND 4-C(buffered) 6.3 95.8 668 3 50 1.7 13 ND ND 4-D (buffered) 6.3 96.2 685 1950 0.7 10 4 ND 4.25% Delfex 5.2 95 348 323 38 4 25 12 ND 4.25% Balance7.0 — 175 49 12 4 14 4 ND

In some embodiments of the invention, the PD solutions are produced withreduced GDPs by using a buffer solution with a bicarbonate (e.g., sodiumbicarbonate). The first vessel 12 contains a PD osmotic agent solutionwith dextrose, sodium chloride, magnesium chloride, calcium chloride,and hydrochloric acid to adjust the pH to 3.0. In one example, thevessel 20 is filled with a concentrated PD lactate buffer solution withlactate only, adjusted to a pH of about 10.0 to about 12.0. Sodiumhydroxide can be used to adjust the pH of the lactate buffer. A suitableconcentration of lactate buffer is 40 mEq/l lactate buffer. In anotherexample, the second vessel 20 is filled with a concentrated PD lactatebuffer solution comprising a bicarbonate buffer, adjusted to a pH ofabout 8.0 to about 9.0. Suitable concentrations are, 37 mEq/l lactatebuffer with 3 mEq/l bicarbonate buffer.

The results obtained by using the methods and compositions of thepresent invention using buffer solutions are summarized in Tables 3 and4.

TABLE 3 Formulation Comparison as Delivered to a Patient FORMULATION,LowCA Bubble PVC Product (mini-bag) bicarb or total Design with Vol Solnlactate NaOH buffer Na Cl Mg Dextrose Bubble [m/l] pH [mEq/l] [mEq/l][mEq/l] [mEq/l] [mEq/l] [mEq/l] [%] 1 Neutral pH PD 6.7 7.4 38.04 1.06of 40 132 95 0.5 1.50% solution, lactate/ NaOH 4.25% NaOH in bubble 2Neutral pH PD 10 7.4 37 3 of 40 132 95 0.5 1.50% solution; lactate/sodium 4.25% bicarb buffer in biacarbonate bubble 3 Delflex (current NA5.3 40 0 40 132 95 0.5 1.50% Product as 4.25% reference) 4 Balance (asNA 7.0 40 0 40 134 101.5 1.0 1.50% reference only) 4.25%

Table 4 shows the results of an average of 3 samples. The concentratedPD lactate buffer was mixed with PVC bag contents containing the PDosmotic agent solution post sterilization. After combining the PDlactate buffer with the PD osmotic agent buffer, the resulting PDsolution was examined and had a significantly reduced amount of AcAcompared with the existing commercially available PD solutions referredto as “Deflex” and “Balance.” Also, by maintaining the pH of the PDosmotic solution at 3.0 and then by adding concentrated PD lactatebuffer at a pH of 10.0 to 12.0, the final pH of the resulting PDsolution was at a more physiologically optimal pH of 7.2 (Table 4).

TABLE 4 GDP Results GDPs (μmole/L) Delflex Balance pH 3 pH 3 (4.25%)(4.25%) Dextrose-side Dextrose-side pH (Final, Mixed) 5.2 6.9 5.3 7.1Buffer Lactate Lac/bic Lactate only Lactate/NaOH 3-DG 348 175 131 106AcA 323 49 15 13 5-HMF 38 12 25 28 Glx 4 4 ND 1 M-Glx 25 14 9 8 FoA 12 2ND 1 Reduction Ratio 0% 65% 76% 80% (%)

Collectively, these demonstrate that by sterilizing a concentrated PDlactate buffer separately from the PD osmotic agent, and then adding theconcentrated PD lactate buffer just before use, the amount of GDPs aresignificantly reduced. In addition, the resulting PD solution has a nearneutral pH of about 7.4 optimized for peritoneal dialysis. Furthermore,the concentrated PD lactate buffer may also contain bicarbonate. Whenthe PD lactate-bicarbonate buffer was added to the PD osmotic agentsolution, the resulting PD solution also had significantly reduced GDPs,and a near neutral pH of about 7.4.

Described above are systems and method meeting the desired objects,among others. It will be appreciated that the embodiments illustratedand described herein are merely examples of the invention and that otherembodiments, incorporating changes thereto, fall within the scope of theinvention. Thus, by way of non-limiting example, it will be appreciatedthat although the first and second agent-containing compartments of theillustrated embodiments are shown as carrying agents of medical PDsolutions), in other embodiments those compartments may contain agentsof other medical or non-medical solutions. Moreover, it will beappreciated that, by way of further non-limiting example, although thetext above describes breaking of the temporary seals (e.g., seals 24,26, 44, 62) by manual manipulation, e.g., of the vessel 20, otherembodiments may be adapted for breaking of those seals by automatedapparatus (e.g., manipulation of the vessel or mini-tube 20 by roboticequipment or otherwise). In this context, what we claim is:

1. A vessel for storing peritoneal dialysis (pd) solutions, comprising:a first compartment containing a first PD agent, a second compartmentcontaining a second PD agent, the second compartment being in any ofdirect and indirect fluid coupling with the first compartment, at leastone of the first and second compartments being adapted to be manipulatedat least partially independently of the other of said first and secondcompartments. a first seal preventing fluid transfer between the firstcompartment and the second compartment, and a second seal preventingfluid transfer between the second compartment and an outlet fluidpathway of the vessel, the vessel adapted to deter breaking of thesecond seal prior to breaking of the first seal.
 2. The vessel of claim1, wherein at least one of the first and second compartments are adaptedto be any of bent, twisted, squeezed and/or folded at least partiallyindependently of the other of said first and second compartments.
 3. Thevessel of claim 1, wherein portions of the vessel in which therespective compartments are formed are at least partially separable fromone another.
 4. The vessel of claim 3, wherein said portions of thevessel are formed so that one such portion can be folded withoutsubstantially folding another such portion.
 5. The vessel of claim 3,wherein said portions of the vessel are formed so that one such portioncan be folded and its respective compartment squeezed withoutsubstantially folding another such portion and squeezing its respectivecompartment.
 6. The vessel of claim 3 formed by stamping, cutting,welding, gluing, or otherwise processing one or more sheets or webs ofPVC or other suitable material to form therein said first and secondcompartments.
 7. The vessel of claim 3, wherein one or more regionsbetween said portions are formed with tearable perforations or tacks. 8.The vessel of claim 7, wherein those perforations and/or tacks areadapted to be torn by the user to partially separate said portions fromone another.
 9. A vessel comprising: a first compartment containing afirst agent of a solution, a second compartment containing a secondagent of the solution, the second compartment being in any of direct andindirect fluid coupling with the first compartment, at least one of thefirst and second compartments being adapted to be manipulated at leastpartially independently of the other of said first and secondcompartments. a first seal preventing fluid transfer between the firstcompartment and the second compartment, and a second seal preventingfluid transfer between the second compartment and an outlet fluidpathway of the system, a protective member coupled to the vessel todeter breaking of the second seal prior to breaking of the first seal.10. The vessel of claim 9 adapted to insure expulsion of at least aportion of the second agent from the second compartment to the firstcompartment prior to breakage of the second seal.
 11. The vessel ofclaim 10, wherein the first chamber and second chamber of the vessel areformed by any one of cutting, welding, stamping, and gluing a sheet orweb of material.
 12. The vessel of claim 11, wherein one or more regionsof the vessel that define the first chamber and second chamber,respectively, are separably affixed to one another by perforations,tacks or the like.
 13. The vessel of claim 12, wherein saidperforations, tacks or the like are adapted to be breakable bymanipulation by a patient, health care provider, or other.
 15. Thevessel of claim 14, wherein the protective member is slidably disposedon the system and adapted to move from a first position, wherein theprotective member inhibits breaking of the second seal, to a secondposition, wherein the protective member does not inhibit breaking of thesecond seal.
 16. The vessel of claim 14, wherein, prior to breaking ofthe first seal, movement of the protective member from the firstposition to the second position is restrained by the second compartment.17. The vessel of claim 16, wherein presence of a quantity of fluid inthe second compartment inhibits the protective member from sliding tothe second position.
 18. The vessel of claim 10, further comprising adiffuser adapted to facilitate mixing of the first agent and the secondagent upon expulsion of the second agent from the second compartment.19. A container system for storing a plurality of fluids, comprising: avessel having a first chamber and a second chamber, the second chamberbeing in any of direct and indirect fluid coupling with the firstchamber, a first seal preventing fluid transfer between the firstchamber and the second chamber, a second seal preventing fluid transferbetween the second chamber and an outlet fluid pathway of the containersystem, and a port fluidly coupling the first chamber and the secondchamber, the port comprising the first seal and a diffuser, the diffuseradapted to facilitate mixing of fluids upon expulsion of fluid from thesecond chamber to the first chamber.
 20. The container system of claim19, wherein the second chamber is adapted to fold upon application offorce and expel fluid contained therein.
 21. The container system ofclaim 19, wherein the container system is adapted to insure expulsion ofat least a portion of fluid from the second chamber to the first chamberprior to breakage of the second seal.
 22. The container system of claim19, further comprising: a protective member adapted to inhibit breakingof the second seal prior to breaking of the first seal.
 23. Thecontainer system of claim 22, wherein the protective member has a slotor other opening sized to slide over at least a portion of the containerforming the second chamber.
 24. The container system of claim 23,wherein the slot or other opening is arranged to slide over at least theportion of the container forming the second chamber only after aquantity of fluid originally present in the second chamber has beenexpelled therefrom.
 25. The container system of claim 23, wherein theslot or other opening is arranged to slide over at least the portion ofthe container forming the second chamber only if the second chamber isat least partially folded.
 26. The container system of claim 19, whereinthe diffuser comprises multiple apertures disposed within the firstchamber.
 27. The container system of claim 26, wherein one or more ofthe multiple apertures extend from a channel that is in fluidcommunication with the second chamber and wherein one or more of theapertures extend at an angle therefrom.